Substituted 5-nitrofuryl-pyrazoles

ABSTRACT

5-Amino-4-cyano-3-(5-nitro-2-furyl)-pyrazoles, substituted in 1position of the pyrazole moiety by alkyl, hydroxyalkyl or carbalkoxy, and pharmaceutically acceptable acid addition salts thereof, have antimicrobial properties; compositions containing these compounds and methods for the treatment of microbial infections and protecting organic material against microbial attack; a typical embodiment is 5-amino-4-cyano-1-methyl-3-(5nitro-2-furyl)-pyrazole.

United States Patent Howarth et al.

[151 3,682,953 1 Aug. 8, 1972 [54] SUBSTITUTED S-NITROFURYL- PYRAZOLES [72] Inventors: Graham Arton Howarth, 13 Hope Avenue, Handforth, Wilmslow, Cheshire; William Hoyle, 61 Valley Road, Bramhall, Cheshire, both of England [22 Filed: Feb. 27, 1970 21 Appl.No.: 15,209

[30] Foreign Application Priority Data March 1, 1969 Great Britain ..l1,064/69 [52] US. Cl. ..260/310 R, 99/2 M, 260/311,

260/347.4, 260/347], 424/273 [51 Int. Cl. ..C07d 49/20 [58] Field of Search ..260/3l0 R, 31 l [56] References Cited FOREIGN PATENTS OR APPLICATIONS 905,459 9/1962 Great Britain ..260/347.7

880,256 10/1961 Great Britain ..260/31OR OTHER PUBLICATIONS Burch J. Med. Chem. Vol. 11, pages 79- 83 (1968), RSlJS.

Sasaki et al. J. Heterocycl. Chem. Vol. 5, pages 243- 8 (1968), QD400J6.

Primary Examiner-Natalie Trousof Att0rneyl(arl F. Jorda and Bruce M. Collins ABSTRACT 7 Claims, No Drawings SUBSTITUTED S-NITROFURYL-PYRAZOLES 9 DETAILED DESCRIPTION wherein R is unsubstituted or hydroxy-substituted alkyl having from one to five carbon atoms, or carbalkoxy having from one to five carbon atoms in the alkyl moiety; as well as to pharrnaceutically acceptable acid addition salts thereof.

The alkyl moiety constituting or forming part of the group R, contains from one to five carbon atoms, but is preferably a straightor branched-chain radical containing from one to three carbon atoms. Examples of alkyl moieties include the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl and n-pentyl groups. If R represents a carbalkoxy group, then it is preferred that it should be an ethoxy-carbonyl group.

The present invention also provides salts of nitrofuryl-pyrazoles of formula I with organic and inorganic acids. Examples of such acids are hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, ethandisulphonic, acetic, trichloroacetic, oxalic, succinic, maleic, fumaric, malic, tartaric, citric and mandelic acids.

The compounds of the present invention are prepared by reacting the corresponding nitrofurylnitrilimine, which in one of its canonical forms may be represented by the formula II,

Ni -o Z 1% e I l with malononitrile.

(III) owl o-x mula III,

wherein X represents a halogen atom, with a base. The process may, if desired, be effected in the presence of a further conventional hydrogen halide acceptor. The halogen present in the halohydrazone of formula III is preferably chlorine or bromine. The nitrofuryl-a-halo-hydrazones of formula III are new compounds. They are produced, for example, by reacting the corresponding nitrofuryl-hydrazones having the formula IV,

OQN-H -CH 0 II N I NHR (IV) with an N-halo compound bearing the requisite halogen.

The present invention also provides a modification of the process for producing a nitrofuryl-pyrazole of formula I, which comprises reacting the corresponding nitrofuryl-hydrazone of formula IV with an N-halo compound and treating the reaction mixture thus ob tained with malononitrile in the presence of a base. In this process of the invention, the intermediate product from the reaction of the nitrofuryl-hydrazone of formula IV with the N-halo compound, is not isolated before contacting with the malononitrile.

The alkyl-substituted hydrazones of formula IV are prepared by reacting 5-nitro-2-furylaldehyde with an alkylor carbalkoxyhydrazine in an anhydrous solvent, e.g. anhydrous ethanol, according to methods described by Howarth et al, J. Org. Chem, 28, 864(1963), Sasaki, Pharm. P. Bull. (Japan), 2, 123(1954) and British Pat. No. 905,459. Hydroxyalkylhydrazones, although new, can also be prepared in a similar manner described in the above-cited references.

Examples of N-halo compounds which may be used in both these processes are N-halo benzotriazoles and N-halo succinimides. Of the N-halo succinimides, the N-chloro compound may be used, but the N-bromo derivative is preferred.

The compounds of the invention having formula I, have valuable antimicrobial properties, and in particular having antibacterial, anthelminthic, antiprotozoal, coccidiostatic, trypanocidal and antimalarial activity of value in human or veterinary medicine. The compounds are particularly valuable in the treatment of infections of the intestinal and urinary tracts. The compounds may also be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial deterioration by contacting, impregnating or otherwise treating the organic material with the compounds in amounts up to about 5 percent by weight. The compounds also find application as growth-promoting additives to animal feedstuffs, to which they may be added in proportions of from 5 to 500 parts per million.

The antimicrobial activity of the compounds of formula I can be demonstrated in a variety of in vitro and in vivo tests. In standard in vitro tests, for example 5- amino-4-cyanol -methyl-3-( 5-nitro-2-furyl )-pyrazole and 5-amino-4-cyano-l -(2-hydroxyethyl)-3-(5-nitro- 2-furyl)-pyrazole, have an excellent inhibiting activity on the growth of Staphylococcus, Escherichia coli, Klebsiella, Salmonella, Candida alb. and other bacteria.

with Staphylococcus aureus, may be described. Groups.

of five albino mice are infected by intraperitoneal injection of 0.2 ml of a suspension of pathogenic germs which causes a mortality rate of 100 percent in a group of untreated control mice. The test compound is ad-v ministered per os by means of a stomach tube, twice on the day of infection. The duration of the therapy is adapted to the virulence of the pathogenic germ. The mice are now observed and the surviving mice are counted on the fourth day. For each dose of the test compound, the cumulative mortality is then calculated according to the method of L]. Reed and M. Muench, Am.J.I-lyg. 27, 493 (1938). From the different mortality rates, the curative dosage necessary for the survival of 50 percent of the test animals, the CD is calculated by the same method of Reed and Muench. The CD thus determined is found to be far below the toxic dose, and indicates that 5-amino-4-cyano-l-( 2-hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole has an excellent activity against Staphylococcus aureus.

For their intended internal use in mammals, the compounds of formula I are administered orally in daily dosages of from about lto about 50 mg/kg, although the exact dosage has to be adjusted to the type of infection, the age, weight and the particular condition of the host being treated.

The compounds of formula I are administered advantageously in form of pharmaceutical compositions comprising an antimicrobially effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

The type of carrier actually used depends to a great extent on the intended application; for external use, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and infections of the mocus membranes caused by bacteria, ointments, powders and tinctures are used in particular. The ointment bases may be anhydrous, for instance they can consist of mixtures of wool fat and soft parafi'm, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are, for instance, rice starch and other starches; the bulk weight of the carriers may be lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum. The tinctures may contain at least one active ingredient of the formula I in aqueous ethanol, in particular 45 to 75 percent ethanol, to which 10 percent to 20 percent of glycerol may be added, if desired. Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also, optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin. The content of active ingredient in pharmaceutical compositions for external application is preferable in the range of from 0.1 percent to 5 percent.

Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth, are suitable for the disinfection of the mouth and throat. The former are preferably prepared from alcoholic solutions containing 1 to 5 percent of active substance to which glycerol or flavorings may be added. Lozenges,

that is solid dosage units, preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2 percent to 20 by weight, as well as the usual conventional additives such a binding agents and flavorings.

Solid dosage units, in particular tablets, drages (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the oral treatment of urinary tract infections. These units preferably contain from 10 to percent of the compound formula I, to enable the administration of daily doses of from 0.1 to 2.5 grams to adults, or of suitable reduced doses to children. Tablets and drage cores are produced by combining the compounds of formula I with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatins, preferably with the addition of lubricants such a magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Drage cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/or titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or mixture of solvents. Dyestuffs can be added to these coatings, for instance to diflerentiate between varying dosages. Soft gelatine capsules and other closed capsules consist, for example, of a mixture of gelatines and glycerol, and may contain, for example, mixtures of the compound of formula I with polyethylene glycol. Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatines, and magnesium stearate or stearic acid.

In all forms for administration, a compound of formula I can be present as sole active ingredient, or it may also be combined with other known pharmacologically active, especially antibacterially and/or antimycotically or otherwise antimicrobially active substances, for example to broaden the range of application. They can be combined for example, with 5,7- dichloro-2-methyl-8-quinolinol or other derivatives of 8-quinolinol, with sulfamerazine or sulfafurazole or other derivatives of sulfanilamide, with chloramphenicol or tetracycline or other antibiotics, with 3,4',-5-tribromosalicylanilide or other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones, with polychloro-hydroxy-diphenylmethanes, with halogen-dihydroxy-diphenyl sulphides, with 4,4- dichloro-2-hydroxy-diphenylether or 2,4,4'-trichloro- 2-hydroxydiphenylether or other polyhalogenhydroxydiphenylethers, or with bactericidal quarternary compounds or with certain dithiocarbamic acid derivatives such as tetramethylthiuram disulphide. Also, carriers, which themselves have favorable pharmacological properties may be used, for instance sulphur as a powder I base or zinc stearate as a compound of ointment bases.

The invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attack which comprises treating the material with a nitrofuryl-pyrazole of formula I. The organic material may be, for instance a natural or synthetic polymeric material, a proteinaceous or carbohydrate EXAMPLE 1 a. To a mixture of 13.1 grams of 5-nitro-2-furaldehyde-a-chloro-N-ethoxycarbonyl-hydrazone and 3.3 grams of malononitrile dissolved in 75 millilitres of methanol is added slowly a mixture of 5.1 grams of triethylamine and 50 millilitres of methanol at 10 C.

After allowing to stand, the crystalline precipitate is collected, washed with water and dried, and is then recrystallized from ethyl acetate. I

The product is 5-amino4-cyano-l-ethoxycarbonyl- 3-(5-nitro-2-furyl)-pyrazole having melting point 207 C.

b. To a stirred mixture of 22.7 grams of 5-nitro-2-furaldehyde N-ethoxycarbonylhydrazone hydrazone and W millilitres of concentrated hydrochloric acid and 20 millilitres of water is added .slowly a solution of 14.2 grams of chlorine dissolved in 100 millilitres of glacial acetic acid at 0 to 10 C.

After further stirring, the mixture is diluted with 1 liter of water and the precipitate is collected, washed with water and dried. The dried solid is recrystallized from toluene.

The product is S-nitro-furaldehyde a-chloro-N'- ethoxycarbonylhydrazone having melting point 125 C.

EXAMPLE 2 l To a stirred solution of 33.8 grams of S-nitro 2-fural- EXAMPLE 3 To a stirred solution of 16.9 grams of 5-nitro-2-furaldehyde N'-methylhydrazone dissolved in 100 millilitres of dimethylforrnamide are slowly added 17.8 grams of N-bromosuccinimide at 20-30 C.

After further stirring, the mixture is cooled to C. To the stirred mixture is then added 6.6 grams of malononitrile followed by the slow addition of a mixture of 10.1 grams of triethylamine and 25 millilitres of dimethylformamide at l0-20 C.

After further stirring, the mixture is diluted with 500 millilitres of iced water and the precipitate is collected, washed with water and dried. The dried solid is recrystallized from ethyl acetate.

6 The product is 5-amino-4-cyano-l-methyl-3-(5- nitro-2-furyl)-pyrazole having melting point 250 C with decomposition.

EXAMPLE 4 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-isopropylhydrazone as starting material-instead of 5-nitro-2-furaldehyde N'- methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-1-is0propyl-3-(5- nitro-2-furyl)-pyrazole.

EXAMPLE 5 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-n-pentylhydrazone as starting material instead of 5-nitro-2-furaldehyde N'- methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-l-(n-pentyl)-3-(5- nitro-2-furyl)- pyrazole.

EXAMPLE 6 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-(2-hydroxyethyl)- hydrazone as starting material instead of 5-nitro-2-furaldehyde N-methylhydrazone, the reaction conditions being the same.

The product is 5-amin0-4-cyanol -(2-hydroxyethyl 3-( 5-nitro-2-furyl)-pyrazole, having melting point 216 C.

EXAMPLE 7 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-ethylhydrazone as starting material instead of S-nitro-Z-furaldehyde N'- methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyanol -ethyl-3-( 5-nitro-2 -furyl)-pyrazole, having melting point 1 89 C.

EXAMPLE 8 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-n-propylhydrazone as starting material instead of S-nitro-Z-furaldehyde N'- methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-3-(5-nitro-2-furyl)- l-n-propyl-pyrazole, having melting point 1 65 C.

EXAMPLE 9 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N-n-pentoxy-carbonylhydrazone as starting material instead of 5-nitro-2-furaldehyde N-methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-3-(5-nitro-2-furyl)- 1 -n-pentoxycarbonyl-pyrazole.

EXAMPLE 10 The procedure described in Example 2 is repeated using 5-nitro-2-furaldehyde N'-(2-hydroxyethyl) hydrazone as starting material in place of 5-nitro-2-furaldehyde N'-methyl hydrazone, the reaction conditions being the same.

-HYDROXYETHYL) hydrazone having melting point 98 C.

EXAMPLE 1 1 Preparation of Tablets 100 g of amino-4-cyano-1-(2-hydroxyethyl)-3-(5- nitro-2-furyl)-pyrazole are mixed with 60.0 g of maize starch and 35.0 g of lactose, the mixture is moistened with a solution of 5.0 g of gelatin and 3.0 g of glycerol in 70.0 g of water and granulated through a sieve. The granulate is mixed with a mixture of 15.0 g of talcum, 10.0 g of maize starch and 2.0 g of magnesium stearate. The resulting mixture is pressed into 1.000 tablets, each containing 100 mg of active substance. If desired, the tablets can be grooved for better adaption of the dosage.

EXAMPLE 12 Preparation of Dragees:

Composition 1 is granulated in the heat with composition 11 through a sieve of 1.2 mm mesh diameter. The dried granulate is mixed with composition Ill and the resulting mixture is pressed into 1.000 drage cores. These are then coated with composition IV and dried. The drages obtained weigh 255.0 mg and contain 100 mg of active substance.

EXAMPLE 13 Preparation of a Syrup Composition: for 1 liter: 5-Amino-4-cyano-l-( 2hydroxyethyl)- 100.0 g 3-( 5-nitro-2-furyl )-pyrazole Colloidal silicon dioxide 13.0 g p-Hydroxybenzoic acid methyl ester 1.4 g p-Hydroxybenzoic acid propyl ester 0.6 g

Citric acid 1.0 g Sodium cyclamate 5.0 g Distilled water 610.0 g Glycerol 100.0 g Sodium carboxymethyl cellulose 4.0 g Sugar 320.0 g

TOTAL l.l55.0 g

er ure filtered, if ecessa and ixed with com- 50535011 l. Water is ad c ied to th result ir ig mixture up to the prescribed weight of 1.1550 g, and the syrup obtained is homogenized.

What is claimed is:

l. A compound of formula l 0.. it.

wherein R is unsubstituted or hydroxy-substituted alkyl having from one to five carbon atoms, or carbalkoxy having from one to five carbon atoms in the alkyl moiety. 2. A pharmaceutically acceptable acid addition salt of a compound according to claim 1.

3. A compound according to claim 1, wherein R is methyl. 4. A compound according to claim 1, wherein R is ethyl. 5. A compound according to claim 1, wherein R is n-propyl. 6. A compound according to claim 1, wherein R is 2-hydroxyethyl. 7. A compound according to claim 1, wherein R is ethoxycarbonyl.

$ ,953 Dated August 8-," 1972 Patent No.

' Inventor(s) GRAHAM ARTON HOWARTH ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, insert [73] Assignee: CIBA-GEIGY Corporation, Ardsley, N.Y.

Column 8, line 26, right side of formula, delete "-CH" and insert CN Signed and sealed this 6th day of August 1971+,

(SEAL) Attest:

c. MARSHALL DANN MCCOY M. GIBSON, JR. Attesti ng Officer Commissioner of Patents- 

2. A pharmaceutically acceptable acid addition salt of a compound according to claim
 1. 3. A compound according to claim 1, wherein R is methyl.
 4. A compound according to claim 1, wherein R is ethyl.
 5. A compound according to claim 1, wherein R is n-propyl.
 6. A compound according to claim 1, wherein R is 2-hydroxyethyl.
 7. A compound according to claim 1, wherein R is ethoxycarbonyl. 